The present invention relates to new salts of morphine, for use as analgesic medicament for relief of pain through electromotive administration.
Morphine is the first opioid drug to have been isolated in pure forme and is used clinically as drug to achieve relief of nocioceptive pain, too severe to be controlled by peripheral analgesics such as the salicylates. Morphine with a pKa of 8.2 units, is strongly ionised at a normal blood pH of 7.4 units and has a low lipid solubility. Therefore this drug is slow to enter the CNS, a fact that is readily verified by having to wait at least 10 minutes after an iv bolus injection to observe maximum respiratory depression.
With detailed pharmachological understanding of agonism-antagonism actions at CNS receptor sites as yet very limited, morphine remains the "gold standard" for assessing the efficacy of all other opioid drugs. It is familiar to physicians the world over, very inexpensive and, given in correct dosages for different painful conditions, always exerts a beneficial therapeutic effect with small chance of inducing psychological dependence.
Morphine base is soluble 1/5000 in water and 1/250 ethanol, thus necessitating ionised formulations for aqueous injections of reasonably small volumes. Two ionised forms, morphine sulphate and morphine hydrochloride, are available for clinical use in most countries. Both formulations are soluble in water, 1/20-25, and their main physical difference is in their solubilities in ethanol, 1/1000 and 1/50, respectively. Many other derivatives of morphine have been synthesised and these include: morphine-hydrobromide; methyl bromide; oxide; nitrate; monobasic phosphate; acetate; lactate; meconate; tartrate; valerate; 6-methylether; oleate; hyperduric; ester-nicotinate and hydrochloride-nicotinate. They proved however to be of little clinical utility.
Of the oral formulations of morphine available, slow-release morphine sulphate has proven particularly valuable in the long term management of cancer pain, although the dose must be adjusted to allow for the 60-70% to be metabolised in the intestinal wall and liver before it ever reaches the systemic circulation and hence the CNS.
Parenteral formulations of morphine are used when oral administration of this agent is presumed ineffectual, classically in post-operative situations. Effective though routine intermittent injections are, they have their disadvantages: blood levels of morphine assume a compound sine-wave shape and, depending upon the frequency and dose of the injections, some patients are alternately obtunded and pain free, or very much alert and in considerable pain. Constant iv infusions with bolus doses on demand resolve the above problem and create others: iv lines occasionally clot and, if sometime later the clot is freed, a patient commencing to feel increasing pain inadvertently receives an excessive dose as a form of bolus injection; in addition, most constant infusions are administered by some form of mechanical pump and more than one patient has died because of "runaway" failure of the pump.
Finally, there are site-selective injections of morphine. Epidural and intrathecal infusions can provide profound regional analgesia with relatively small doses. However, these techniques require supervision by specialists well versed in the art of infusions in and around the spinal cord.
From the foregoing, it is apparent that a new mode of administration of morphine is desireable which permits both to bypass the vagaries of intestinal absorption and the first pass effect through the liver, and also to avoid the mechanical and infective problems associated with invasive parenteral technologies.
Passive transdermal administration of fentanyl has been described by Gale et al (U.S. Pat. No 4,588,580) and Cleary (U.S. Pat. No 4,911,916), while Aungst et al (EPA No 85109909.3) claimed a similiar technique for the administration of some 13 opioids and opioid antagonists. Passive transdermal administration of a drug, for example by patch application, relies ultimately on the concentration gradient to determine the rate of drug delivery and herein lie the advantages of this form of drug administration: it is the essence of simplicity with no delivery device to malfunction; in theory at least, blood levels of drugs reach a plateau and then maintain constant levels for many hours, or even days, on end; non-compliance by patients diminishes from a major to a minor issue.
In spite of these undeniable advantages, passive transdermal administration of opioids has some pertinent disadvantages: there is a time interval of at least 6 hours between the application of a fentanyl patch and the appearance of therapeutic blood levels, obviously rendering this technique useless for an acute situation; furthermore, this interval varies so widely that the patches are rarely used in post-operative situations where patients receive their opioids by the more controllable iv or im injections; finally, although the rate of fentanyl absorption is fairly constant for any one individual, the rates of absorption between two similiarly sized individuals may vary by as much as 100%, which adds to the uncertainty when these patches are applied for the first time.
Electromotive administration of drugs eliminates the most prominent disadvantages of passive transdermal drug delivery. For the purposes of this invention, Electromotive Drug Administration (EMDA) is defined as the combined or additive effects of iontophoresis and electrophoresis upon drug transport. As is known, iontophoresis is the active transport of ionised molecules into tissue by the passage of an electric current through a solution containing the ions, using an appropriate electrode polarity. Usually, the electrical driving force of administration is totally predominant over passive diffusion of the (drug) ions, leading to a greatly accelerated controllable rate of drug administration. In addition, iontophoresis is associated with increased transport of water into tissues (electroosmosis) which may induce an enhanced penetration of electrolytes (down their coulombic gradients) and non electrolytes or even the transport of electrolytes against their coulombic gradients, as described by Petelenz et al. (Journal of Controlled Release 1992; 20: 55-66). For the purposes of this invention and in accordance with Sibalis (U.S. Pat. No. 4,878,892), this phenomenon is termed electrophoresis and is a form of "solvent drag" where the gradient of the chemical potential for water activates both a flow of water and of solute dissolved in water. Usually the effect of iontophoresis predominates over electrophoresis with ionised drugs as, for example, drugs in the form of their water soluble salts.
Thus, it may be anticipated that EMDA of ionised drugs, for example of opioids such as of morphine, will result in accelerated administration rates with a consequent rapid rise of blood levels into the therapeutic range; the interval of time required to attain therapeutic blood levels is quite constant for individuals of similiar bodily mass when the same current strengths and times of application are used; rates of opioid administration in different individuals depend solely upon the two controllable variables, current and time, not upon the totally uncontrollable vagaries of skin texture and thickness. The feasibility of iontophoretic administration of morphine has been demonstrated in clinical settings by Petelenz et al (U.S. Pat. Nos. 4,752,285 and 4,915,685); and by Ashburn et al, (J. Pain and Sympton Management 1992; 7(1):27-33) whose investigations showed clinically effective blood levels of morphine within 15-20 minutes of application of electric current. Petelenz et al (Transdermal drug delivery system for applications in space flight: Phase I Report. NASA SBIR Aug. 31, 1990) also conducted laboratory experiments with iontophoresis of fentanyl into and across hairless mouse skin.
All of the above investigations were successful in that therapeutic administration rates of the two opioids were achieved for periods of time extending into hours. Nevertheless, there were several well known iontophoretic problems to be solved before the desired results could be obtained. Charge transfer must take place at the solid conductor-electrolyte interface and, at the anode, there are only two mechanisms for charge transfer: dissolution of anodic metals adding metallic ions to the drug solution; or, with an anode of inert material, the build up of an electrical double layer at the interface causing the potential to rise until there is electrolysis of water, hydrogen ions (H.sup.+) and gaseous oxygen (O.sub.2). Both producing situations result in additional undesireable ions within the drug solution competing for electric charge and diminishing efficiency of drug delivery. Also, excessive quantities of H.sup.+ rapidly acidify the electrode contents, possibly changing the chemical structure of the drug and eventually damaging the underlying skin. To avoid these problems, two different approaches were used. The first was the selection of the hydrochloride salt of morphine (MHCl ) combined with the use of a silver anode, so that dissolution of silver into silver ions (Ag.sup.+) resulted in the immediate precipitation of insoluble silver chloride (AgCl), thereby removing competitive Ag.sup.+ and avoiding generation of H.sup.+ (U.S. Pat. No. 4,752,185). The second approach was the attachment of the medication (morphine) to an ion exchange matrix so that when the drug ion left the matrix the vacated active sites were occupied by products of electrolysis which was purposely engendered at the anode-drug solution interface (U.S. Pat. No. 4,915,685).
Although these two techniques lead to satisfactory results in the laboratory and in a limited number of patients involved in clinical investigations, there are additional problems to be overcome. The silver-MHCl combination is very inefficient (9%-12%), i.e. shows a low current efficiency in drug transport, which is tolerable, and also leaves a great proportion of the morphine (80%-90%) remaining unused in the electrode-receptacle, which will create major problems in disposal if used on a wide scale. An ion exchange matrix, resin or membrane, theoretically will provide almost 100% utilization of morphine, however, preparation of both the drug itself and the drug containing electrode-receptacle increases the complexity of the apparatus.